Cobalt-Catalyzed Asymmetric Hydrogenation of Enamides: Insights into Mechanisms and Solvent Effects

The mechanistic details of the (PhBPE)Co-catalyzed asymmetric hydrogenation of enamides are investigated using computational and experimental approaches. Four mechanistic possibilities are compared: a direct Co(0)/Co(II) redox path, a metathesis pathway, a nonredox Co(II) mechanism featuring an aza-metallacycle, and a possible enamide–imine tautomerization pathway. The results indicate that the operative mechanism may depend on the type of enamide. Explicit solvent is found to be crucial for the stabilization of transition states and for a proper estimation of the enantiomeric excess. The combined results highlight the complexity of base-metal-catalyzed hydrogenations but do also provide guiding principles for a mechanistic understanding of these systems, where protic substrates can be expected to open up nonredox hydrogenation pathways.

In a nitrogen-filled glovebox, a thick-walled glass vessel was charged with MAA (0.014 g, 0.10 mmol), (S,S)-( Ph BPE)CoCl2 (0.002 g, 0.003 mmol, 3 mol%), Zn (0.007 g, 0.10 mmol, 100 mol%), MeOH (1.5 mL), and a stir bar. The vessel was sealed and removed from the glovebox. On a high-vacuum line, the solution was frozen and the head-space removed under vacuum. The vessel was back-filled with 4 atm of H2. The solution was sealed, thawed, and stirred at 50 °C in an oil bath for 18 hours. Following this time, the reaction was air-quenched and the solvent evaporated. The crude mixture was taken up in CDCl3 and filtered through an alumina plug. The resulting sample was analyzed by 1 H NMR and chiral GC.

HD experiments MAA
In a nitrogen filled glovebox, a 4 mL vial was charged with a MeOH solution (total volume for each trial was equal to 2 mL) with enamide (0.20 mmol), (R,R)-( Ph BPE)-Co-(COD) or (R,R)-( Ph BPE)-CoCl2 (0.04 mmol, 2 mol%; and Zn (20 mol%) when the dihalide was used), and a stir bar. The vial was then placed into a high-pressure reactor, sealed, and removed from the glovebox. The reactor was backfilled with 60 psi of HD and allowed to react for 5 days. At this point the reaction was air-quenched and the volatiles were evaporated under air. The residue was then taken up with EtOAc and filtered through an alumina plug. The solvent was removed, and the residue was taken up in CHCl3 or CDCl3. Deuterium incorporations were determined using 1 H, 2 H, and quantitative 13 C NMR spectroscopy.       Figure S10. Full quantitative 13 C NMR of the product of reaction of MAA with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction) (rt, CDCl3). Figure S11. Section of the quantitative 13 C NMR of the product of reaction of MAA with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction) (rt, CDCl3). Figure S12. Section of the quantitative 13 C NMR of the product of reaction of MAA with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction) (rt, CDCl3). Figure S13.  Figure S16. Full quantitative 13 C NMR of the product of reaction of DHL with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction) (rt, CDCl3). Figure S17. Section of the quantitative 13 C NMR of the product of reaction of DHL with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction). Figure S18. Section of the quantitative 13 C NMR of the product of reaction of DHL with HD catalyzed by Ph BPE-CoCl2 (with in-situ Zn reduction) (rt, CDCl3).

H2/D2 Scrambling
In a nitrogen filled glovebox, a J. Young NMR tube was charged with a C6D6 (0.5 mL) solution of (R,R)-( Ph BPE)-Co-(COD) (0.010 g, 0.015 mmol) (tube 1). A second J. Young NMR tube was sealed but left empty (tube 2). The tubes were removed and taken to a high-vacuum line. The solution in tube 1 was frozen, and the headspace removed under vacuum. The tube was back-filled with 4 atm of H2, and the solution was kept frozen. Tube 2 was similarly evacuated and backfilled with 4 atm of D2. The two tubes were subsequently placed on a two-port, which was evacuated in the middle. The gasses of both tubes were allowed to mix for 10 minutes with the solution still frozen, after which tube 1 was sealed, thawed, and mixed. The contents were analyzed by 1 H NMR.

A) B)
Figure S19. A) 1 H NMR spectra of Ph BPE-Co-(COD) before and after addition of H2 and D2 (rt, C6D6). B) Section of 1 H NMR spectra of Ph BPE-Co-(COD) before and after addition of H2 and D2 (rt, C6D6).

Computational details
All calculations were performed with the Gaussian09 package, Rev. D01. 2 The DFT hybrid functional B3LYP 3,4 was employed with the Grimme empirical dispersion correction (D3). 5 Additional calculations were carried out with two different computational protocols, PBE0 6,7 -D3BJ 8 and ωB97XD 9 , to check the robustness of the obtained results. The IEFPCM model was used in all calculation in order to include solvent effects (methanol solvent). [10][11][12][13] For the geometry optimizations, the small 6-311G (d,p) 14 (BS1) basis set was used on all non-metals, whereas the basis set and the pseudopotential LANL2TZ 15 was used on Co. In order to obtain more accurate energies, single point calculations were performed with 6-311++G(2df,2pd) on all non-metals, whereas the basis set and the pseudopotential LANL2TZ was used on Co (BS2).
Counter poise corrections 16,17 were computed at the BS2 level (CPBS2) to correct for the artificial lowering of the electronic energy, caused by the borrowing of basis functions when molecular fragments are joined into one model. This correction was computed for the following steps: addition of H2, MeOH, MAA or DHL to the model. For the addition of H2, the CP corrections were computed at three levels of theory (CP = 0.9 kcal/mol for B3LYP-D3; CP = 0.9 kcal/mol for PBE0-D3BJ, CP = 0.8 kcal/mol for wB97XD). For the addition of MeOH, CP = 0.8 kcal/mol at the B3LYP-D3 level of theory. The CP corrections for the addition of MAA and DHL were 3.9 kcal/mol and 3.1 kcal/mol, respectively, at the B3LYP-D3 level of theory.
The computed free energies (ΔG°1atm, BS1) in the gas phase were converted into the corresponding 1M standard state energies, employing a standard state (SS) conversion term. 18 Only reactions where the number of moles are changed are affected. For the reaction A + B = C at 323.15 K, SS = -2.1 kcal/mol. For reactions involving explicit solvent, the standard state of the solvent is employed, which is 4.2 kcal/mol (based on the concentration of the pure solvent of 24.7 M for MeOH, derived from the density of 0.792 g/mL). Temperature corrections were included in all free energies to match the experimental temperature (50 °C). The standard state Gibbs free energies (ΔG°1M,323K) reported in the main text correspond to: (eq.1) ΔG°1M,323K = ΔG1atm, 323K,BS1 -ΔE1atm,BS1 + ΔE1atm,BS2 + CPBS2 + SS323K Enantiomeric excesses were evaluated from the computed barriers for the rate limiting steps using the following formula: 19 Figure S20. Evaluation of the Co-enamide interaction strength (B3LYP-D3[IEFPCM(methanol)], kcal/mol, 323 K).

Alternative mechanisms for the hydrogenation of dehydrolevetiracetam (DHL)
9. Redox Co(0)-Co(II) mechanism A for the hydrogenation of DHL Figure S21. Mechanism and computed free energies (B3LYP-D3[IEFPCM(methanol)], kcal/mol, 323 K, relative to Co-Sub) for Ph BPE-Co-catalyzed hydrogenation of DHL via mechanism A, where oxidative hydride transfer occurs to the Cβ atom via TS-Hyd. This step is rate-limiting, with a barrier of 27.4 kcal/mol for the formation of the (S)-product. In the final step, reductive elimination occurs in order to liberate the product and regenerate the catalyst. This step has a barrier of 23.5 kcal/mol for the (S)-pathway, assuming that the (R) and (S) intermediates are not in equilibrium (due to the high backwards barrier), and 24.3 kcal/mol if they are assumed to be in equilibrium.

S22
10. σ-bond metathesis mechanism B for the hydrogenation of DHL Figure S22. Mechanism and computed free energies (B3LYP-D3[IEFPCM(methanol)], kcal/mol, 323 K, relative to Co-Sub) for Ph BPE-Co-catalyzed hydrogenation of DHL via a σbond metathesis mechanism B. After formation of chelate intermediate, coordination of H2 occurs, followed by a proton transfer to Cα, which is the rateand selectivity-determining step. The overall barrier for formation of the (S)-product (relative to the lowest lying intermediate) is 37.7 kcal/mol. S23 11. Computed mechanism for the hydrogenation of DHL via mechanism C with a 4-membered metallacycle (mechanism C(m4))  12. Mechanism C for the hydrogenation of DHL with hydride transfer to Cα and formation of a 5-membered metallacycle (mechanism C(m5)) Figure S24. A) Mechanism and computed free energies (B3LYP-D3/[IEFPCM(methanol)], kcal/mol, 323 K, relative to Co-Sub) for Ph BPE-Co-catalyzed hydrogenation of DHL via a 5membered metallacycle mechanism C(5m) where hydride transfer to the Cα atom occurs first. The barriers for this step are 20.3 kcal/mol and 23.7 kcal/mol, for pro-(R) and pro-(S) TSs, respectively. Then, H2 coordination takes place, followed by proton transfer to the Cβ atom, forming a Co(II)-H-intermediate. The computed barriers for this step are 23.3 kcal/mol and 24.9 kcal/mol for pro-(S) and pro-(R) TS structures. Finally, coordination of another substrate occurs, which transfers its proton to the nitrogen atom, resulting in the final product and the regeneration of the active Co(II)-monohydride species. The rate-limiting step for the formation of (S)-product is hydride transfer to Cα (23.7 kcal/mol, with the subsequent proton transfer being close in energy, 23.3 kcal/mol), whereas for the formation of (R)-product, it is proton transfer to Cβ (24.9 kcal/mol, relative to the pro-(S)-Metallacycle). Energies in parenthesis with green color are from computational models including an explicit MeOH molecule hydrogenbonded to the substrate. We note that all barriers are computed assuming Curtin-Hammett conditions, implying that intermediates along the (R)-and (S)-pathways can interconvert. There exist also the possibility that formation of the Co-monohydride or Co-metallacycle is not reversible (non-Curtin Hammett conditions), the analysis of the e.e. in that case is beyond the scope of this work.

14.
A direct oxidative addition of the ionizable group of the substrate to Co(0) giving Co(II)-monohydride , kcal/mol, 323 K, relative to Co-Sub) for Ph BPE-Co-catalyzed hydrogenation of MAA via mechanism A where oxidative hydride transfer occurs to the Cα atom via TS-Hyd (compared to Cβ in the main text). The rate limiting step the proton transfer to Cβ with a barrier of 36.3 kcal/mol. Evaluated is only the reaction pathway that will give the (S)-product. S28 18. σ-bond metathesis mechanism B for MAA; hydride transfer to Cβ Figure S28. Mechanism and computed free energies (B3LYP-D3[IEFPCM(methanol)], kcal/mol, 323 K, relative to Co-Sub) for Ph BPE-Co-catalyzed hydrogenation of MAA via σbond metathesis mechanism B, in which after formation of chelate intermediate, coordination of H2 occurs, followed by proton transfer to Cα, which the rate-and selectivity-determining step. The overall barrier for formation of the (R)-product is 32.7 kcal/mol and 28.6 kcal/mol for the (S)-product (for the latter assuming the chelate intermediates are not in equilibrium, if they are, the (S)-barrier increases to 29.9 kcal/mol). S29 19. 6-membered metallacycle mechanism C(6m) for MAA, hydride transfer to the Cα In the next step, either proton transfer to N or to Cβ may occur. The barriers are 35.9 kcal/mol and 24.9 kcal/mol, respectively, indicating that proton transfer occurs to Cβ, which is found to be rate-limiting step. We also tested if addition of an explicit MeOH molecule that hydrogen bonds to the substrate changes the barriers of mechanism C (energies in parenthesis with green color are from computational models including an explicit MeOH molecule hydrogen-bonded to the substrate). In presence of explicit MeOH, the rate-limiting step is the proton transfer to Cβ, with barriers of 21.8 kcal/mol and 24.3 kcal/mol, for the pro-(S) and pro-(R) TSs, respectively. 24. Proposed mechanism for the formation of the active Co(II)-metallacycle_H 2 species via an imine intermediate Figure S33. An investigated mechanism for the formation of an active catalyst species via an imine intermediate (B3LYP-D3[IEFPCM(methanol)], kcal/mol, 323 K, relative to Co-Sub). In the next step H2 binds, followed by hydride transfer to the Cα atom. After formation of Co(II)-Int-H, a hydride may abstract a proton of the methyl group. This mechanism is excluded due to a very high barrier of 40.5 kcal/mol. Energies in parenthesis with green color are from computational models including an explicit MeOH molecule hydrogen-bonded to the substrate.

S34
25. MeOH mediates proton transfer from NH 2 of the Co(0)-enamide giving either 6-mem. metallacycle or Imine intermediates  31. An alternative metallacycle mechanism C (4m) for DHL where MeOH delivers a proton to the nitrogen of the product Figure S39. Metallacycle mechanism C(4m) ( Figure S21) and C(5m) (Figure S24).  (Figures 5, S36) and via mechanism C(6m) (Figure S29).  Table S4. Comparison of doublet and quartet spin states for critical structures, including the energetic reference state Co-enamide and the rate-limiting transition states of Mechanism A and C(6m) for MAA (free energies in kcal/mol at 323 K, B3LYP-D3, with SS and CP corrections, geometries without explicit MeOH). The quartet states are between 11.8 and 14.7 kcal/mol higher than the corresponding doublet states, making it highly unlikely that quartet states play a role in the catalytic cycle.

Evaluation of quartet spin states
a Figure S36, TS_Hyd, b Figure S29